Reversal of neuropathic pain by alpha-hydroxyphenylamide: a novel sodium channel antagonist.

Abstract

Sodium (Na) channel blockers are known to possess antihyperalgesic properties. We have designed and synthesized a novel Na channel antagonist, alpha-hydroxyphenylamide, and determined its ability to inhibit both TTX-sensitive (TTX-s) and TTX-resistant (TTX-r) Na currents from small dorsal root ganglion (DRG) neurons. alpha-Hydroxyphenylamide tonically inhibited both TTX-s and TTX-r Na currents yielding an IC(50) of 8.2+/-2.2 microM (n=7) and 28.9+/-1.8 microM (n=8), respectively. In comparison, phenytoin was less potent inhibiting TTX-s and TTX-r currents by 26.2+/-4.0% (n=8) and 25.5+/-2.0%, respectively, at 100 microM. alpha-Hydroxyphenylamide (10 microM) also shifted equilibrium gating parameters of TTX-s Na channels to greater hyperpolarized potentials, slowed recovery from inactivation, accelerated the development of inactivation and exhibited use-dependent block. In the chronic constriction injury (CCI) rat model of neuropathic pain, intraperitoneal administration of alpha-hydroxyphenylamide attenuated the hyperalgesia by 53% at 100mg/kg, without affecting motor coordination in the Rotorod test. By contrast, the reduction in pain behavior produced by phenytoin (73%; 100mg/kg) was associated with significant motor impairment. In summary, we report that alpha-hydroxyphenylamide, a sodium channel antagonist, exhibits antihyperalgesic properties in a rat model of neuropathic pain, with favorable sedative and ataxic side effects compared with phenytoin.

• Authors: Seong-Hoon Ko, Nina Jochnowitz, Paul W Lenkowski, Timothy W Batts, Gary C Davis, William J Martin, Milton L Brown, Manoj K Patel
• Journal: Neuropharmacology (Neuropharmacology) Vol. 50 Issue 7 Pg. 865-73 (Jun 2006) ISSN: 0028-3908 [Print] England
• PMID: 16464480 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-hydroxy-2-phenylnonanamide
• Amides
• Sodium Channel Blockers
• Sodium Channels
• Phenytoin

Topics

• Action Potentials (drug effects, physiology)
• Amides (chemistry, pharmacology, therapeutic use)
• Animals
• Dose-Response Relationship, Drug
• Ganglia, Spinal (drug effects, physiology)
• Male
• Pain (drug therapy, physiopathology)
• Phenytoin (analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sciatic Neuropathy (drug therapy, physiopathology)
• Sodium Channel Blockers (chemistry, pharmacology, therapeutic use)
• Sodium Channels (physiology)